Role of hypoxia in promotion of higher grade glioblastoma

Summary of Project:

Glioblastomas are categorized into four grades. Grade I is essentially benign and slow growing, and most amenable to treatment. Grade II tumors are larger and invade surrounding tissue. The two lower grade gliomas show little necrosis and vascular proliferation. Grade III gliomas are malignant and demonstrate foci of high vascular proliferation with a defined necrotic core that expands rapidly in grade IV to afford a highly malignant, heterogeneous and invasive cancer (glioblastoma multiforme or GBM).

Progression to higher grade gliomas is irreversible, and at grades III and IV, treatment options for the disease are very limited. As a result, median survival rate for patients suffering from grade IV glioma is below 15 months. Understanding the mechanisms by which glioma progresses from lower grades 1 and 2 to higher grades 3 and 4 is important in order to devise new and more efficient therapeutic interventions, and to identify biomarkers for disease progression, so existing therapeutic interventions can be more appropriately applied.Of particular interest to us is the chemotactic formyl peptide receptor-1 (FPR-1), which is activated by short chain N-formylated peptides (e.g. fMLF) and annexin A1. Interestingly, in cancer cell lines, much of the pathophysiological effects of the activation of FPR-1 appear to be directly relevant for the differences observed between lower and higher grade gliomas.

Hypothesis

We have hypothesised that the progression from lower to higher grade gliomas is associated with the development of a hypoxic, necrotic core in the tumour as it expands., Lack of nutrients and oxygen (hypoxia) within the expanding tumour drives necrosis. Hypoxia also drives the expression of FPR-1, whilst necrosis results in the release of chemotactic peptide agonists for FPR-1. The combination of these two events enables cells to acquire a more invasive, malignant and death-resistant phenotype, which is characteristic of higher grade glioma.

Objectives of PhD study:

We will detect proteins of interest using immunohistochemistry on frozen or paraffin embedded tissue. Proteins of interest include FPR-1 and Annexin A1, as well as Ki67 (as a marker of proliferation), MMP-9 and EGFR (markers of malignancy), pimonidazole, HIF-1α, CAIX, LDH-5, and GLUT-1. GFAP will be used to identify glial cells. We will assess the correlation between FPR-1 expression and these key markers for hypoxia, necrosis and tumour expansion.

Multicellular spheroids of glioma cells with diameters between 200-800 microns are prepared in our lab; we will expand on this work and compare the expression of the same proteins in the spheroid cores, thus establishing the validity of the spheroids without a hypoxic core and with hypoxic core as in vitro models for low and high grade glioblastomas respectively.

Antagonists from our FPR-1 antagonist program will be evaluated in an iterative process in such models.

Relevance and context:

Our group is very active in the discovery of new cancer agents. Specifically, we have been engaged in the study of potent FPR-1 antagonists, as a new treatment for glioblastoma.

This project will provide further evidence in support of our disease hypothesis; therefore, this project strongly supports existing lines of research currently within our group.

Cancer research and drug discovery is a research focus area in the Faculty of Life Sciences and an area of strength as evident with the activities of ICT. This project strengthens the research in ICT and faculty by contributing to the development of new agents, supporting an already established target and thus consolidating the pipeline of new agents from ICT.

Funding:

Applicants will need to have their own funding or external sponsorship. A bench fee is required in addition to the tuition fees.